Age-related macular degeneration (AMD) causes progressive impairment of central vision and is the leading cause of irreversible vision loss in older Americans(1). The most severe form of AMD involves neovascular/exudative (wet) and/or atrophic (dry) changes to the macula. Although the etiology of AMD remains largely unknown, implicated risk factors include age, ethnicity, smoking, hypertension, obesity and diet (2). Familial aggregation (3), twin studies (4), and segregation analysis(5) suggest that there is also a significant genetic contribution to the disease. The candidate gene approach and genome-wide association studies have consistently implicated the CFH, ARMS2 and C2/BF genes, all members of the complement-mediated inflammatory cascade.
Age-related macular degeneration (AMD) is a common complex disorder that affects the central region of the retina (macula) and is the leading cause of legal blindness in older American adults. The prevalence of AMD and its significant morbidity will rise sharply as the population ages. AMD is a clinically heterogeneous disorder with a poorly understood etiology. Population-based longitudinal studies(6-8) have established that the presence of extracellular protein/lipid deposits (drusen) between the basal lamina of the retinal pigment epithelium (RPE) and the inner layer of Bruchs' membrane is associated with an increased risk of progressing to an advanced form of AMD, either geographic atrophy or exudative disease. The presence of large and indistinct (soft) drusen coupled with RPE abnormalities is considered an early form of the disorder and is often referred to as age-related maculopathy (ARM).
Epidemiology: AMD is a complex disorder with contributions of environmental factors as well as genetic susceptibility(2). Many environmental and lifestyle factors have been postulated, but by far the most consistently implicated non-genetic risk factor for AMD is cigarette smoking (6). Much progress has been made in identifying and characterizing the genetic basis of AMD. In a remarkable example of the convergence of methods for disease gene discovery, multiple independent research efforts identified the Y402H variant in the complement factor H(CFH [(MIM 134370]) gene on chromosome 1q32 as the first major AMD susceptibility allele (9-14). While one of the studies was able to pinpoint CFH on the basis of a whole-genome association study (11), most studies focused on the 1q32 region because it had consistently been implicated by several whole-genome linkage scans. Disease associated haplotypes within the CFH gene are also associated with AMD (15). A second genomic region with similarly consistent linkage evidence is chromosome 10q26, which was identified as the single most promising region by a recent meta-analysis of published linkage screens (16).
Two studies have suggested specific AMD susceptibility genes located on chromosome 10q26. One used a combination of family-based and case-control analyses to implicate the PLEKHA1 gene (pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 1 [MIM 607772]) and the predicted ARMS2 gene (14;17;18). ARMS2 appears to be a mitochondrial membrane protein involved in inflammation (19) A second study using two independent case-control datasets concluded that the T allele of SNP rs10490924 in ARMS2, a coding change (Ala69Ser) in exon 1 of this gene, was the most likely AMD susceptibility allele (16). Both studies reported that the chromosome 10q26 variant confers an AMD risk similar in magnitude to that of the Y402H variant in CFH. A locus with less strong association, but reproducible association with AMD is the complement component 2 (C2) and Factor B (C2/BF) locus within the major histocompatability complex III locus found on chromosome 6 The L9H variant of BF and the E318D variant of C2, as well as a variant in intron 10 of C2 and the R32Q variant of BF, confer a significantly reduced risk of AMD (20).